Immunosuppressive agents are widely utilized as a treatment agent for autoimmune diseases such as rheumatoid arthritis, nephritis, degenerative knee arthritis, and systemic lupus erythematosus, chronic inflammatory diseases such as inflammatory bowel disease, and allergic diseases such as asthma and dermatitis. In particular, with the progress in medical technology, in recent years large numbers of transplant operations of tissues, organs and the like are being performed. In such medical practice, whether the post-transplant rejection reaction can be well controlled determines whether the transplant is successful or not. Immunosuppressive agents are playing an important role in this area as well.
In organ transplants, antimetabolites represented by azathioprine and mycophenolate mofetil, calcineurin inhibitors represented by cyclosporine A and tacrolimus, and adrenocortical hormones represented by prednisolone are used. However, in some cases the effectiveness of these pharmaceuticals has been insufficient, or blood concentration monitoring has been essential in order to avoid serious side effects such as kidney damage. Therefore, in terms of their effectiveness and side effects, these pharmaceuticals have not always been satisfactory.
Furthermore, to alleviate the side effects of the immunosuppressive agent and to obtain a sufficient immunosuppressive activity, multiple drug therapy using a plurality of pharmaceuticals having different action mechanisms is typical. Thus, there is also a need for development of a new type of pharmaceutical which has an action mechanism different from that of the above-described immunosuppressive agents.
Recently, reports of various amino alcohol derivatives, such as 2-amino-1,3-propanediol derivatives and 2-aminoethanol derivatives, as novel immunosuppressive agents have been drawing attention. However, these amino alcohol derivatives themselves do not have an immunosuppressive activity. These drugs are metabolized after being administered into the body to produce a phosphate, and it is this phosphate which is the true physiologically active substance. The produced phosphate exhibits agonistic activity and antagonist activity against various sphingosine 1-phosphate (S1P) receptors. Among them, in 2002 it was reported for the first time that the agonistic activity against S1P1 receptors expresses an immunosuppressive activity by regulating white blood cell migration (Non-patent Documents 1 and 2). It has also been disclosed that, in addition to being effective for various organ transplants and GVHD, the series of derivatives introduced in these Non-patent documents are effective for rheumatoid arthritis, lupus nephritis, systemic lupus erythematosus, chronic thyroiditis, multiple sclerosis, myasthenia gravis, type I and II diabetes mellitus, autoimmune diseases such as Crohn's disease, allergic diseases such as atopic dermatitis, allergic rhinitis, allergic conjunctivitis, and allergic contact dermatitis, and inflammatory diseases such as inflammatory bowel disease or ulcerative colitis (Patent Documents 1 and 2). Since these reports, not only amino alcohol derivatives, but various compounds, such as amino phosphate derivatives and amino carboxylic acid derivatives, have been disclosed as immunosuppressive agents or S1P1 to S1P5 receptor regulators focused on S1P1 receptors (Patent Documents 3 to 66).
Furthermore, since S1P4 receptors are largely concentrated in immunocompetent cells, such as leukocytes, and in organs which greatly contribute to the immune system, it is suggested that S1P4 receptors have a strong contribution to the immune system. In fact, compounds having an S1P4 agonistic activity have been disclosed for autoimmune diseases such as SLE and rheumatism, asthma, allergic diseases such as atopic dermatitis, and inflammatory disease remedies (Patent Documents 34, 39, and 50).
Thus, while a great deal of attention is being paid to S1P receptor agonist drugs which may have hidden potential in a wide variety of medical applications, not all S1P receptor agonist drugs provide a desirable action on the body.
For example, an S1P receptor agonist drug which has exhibited effectiveness in clinical trials in suppressing organ transplant rejection was found to produce bradycardia as a side effect after administration. This effect was reported to probably be caused by agonistic activity against the S1P3 receptor (Non-patent Documents 3 and 4). Furthermore, agonistic activity against the S1P3 receptor has also been reported to cause in experimental animal models effects such as obstruction of myocardial blood flow (Non-patent Document 5), cerebral arterial spasms (Non-patent Document 6), and pulmonary edema (Non-patent Document 7).    [Patent Document 1] WO 0218395 pamphlet    [Patent Document 2] WO 02076995 pamphlet    [Patent Document 3] WO 9408943 pamphlet    [Patent Document 4] Japanese Patent Application Laid-Open No. Hei 9-2579602    [Patent Document 5] WO 0206268 pamphlet    [Patent Document 6] Japanese Patent Application Laid-Open No. 2002-53572    [Patent Document 7] Japanese Patent Application Laid-Open No. 2002-167382    [Patent Document 9] WO 02076995 pamphlet    [Patent Document 10] Japanese Patent Application Laid-Open No. 2003-137894    [Patent Document 11] WO 03040097 pamphlet    [Patent Document 12] WO 02064616 pamphlet    [Patent Document 13] WO 02062389 pamphlet    [Patent Document 14] Japanese Patent Application Laid-Open No. 2002-316985    [Patent Document 15] Japanese Patent Application Laid-Open No. 2003-267936    [Patent Document 16] WO 03051876 pamphlet    [Patent Document 17] WO 03061567 pamphlet    [Patent Document 18] WO 03062248 pamphlet    [Patent Document 19] WO 03062252 pamphlet    [Patent Document 20] WO 03073986 pamphlet    [Patent Document 21] WO 03074008 pamphlet    [Patent Document 22] WO 03105771 pamphlet    [Patent Document 23] WO 04010949 pamphlet    [Patent Document 24] WO 04024673 pamphlet    [Patent Document 25] WO 04058149 pamphlet    [Patent Document 26] WO 04071442 pamphlet    [Patent Document 27] WO 04096752 pamphlet    [Patent Document 28] WO 04096757 pamphlet    [Patent Document 29] WO 04103279 pamphlet    [Patent Document 30] WO 04103306 pamphlet    [Patent Document 31] WO 04103309 pamphlet    [Patent Document 32] WO 04110979 pamphlet    [Patent Document 33] WO 04113330 pamphlet    [Patent Document 34] WO 04074297 pamphlet    [Patent Document 35] WO 05014603 pamphlet    [Patent Document 36] WO 05020882 pamphlet    [Patent Document 37] WO 04002531 pamphlet    [Patent Document 38] WO 05032465 pamphlet    [Patent Document 39] WO 05041899 pamphlet    [Patent Document 40] WO 05058848 pamphlet    [Patent Document 41] WO 05070886 pamphlet    [Patent Document 42] WO 05082089 pamphlet    [Patent Document 43] WO 05082841 pamphlet    [Patent Document 44] WO 05021503 pamphlet    [Patent Document 45] WO 05040091 pamphlet    [Patent Document 46] WO 05085179 pamphlet    [Patent Document 47] WO 05118523 pamphlet    [Patent Document 48] WO 05014525 pamphlet    [Patent Document 49] WO 06020951 pamphlet    [Patent Document 50] WO 06001463 pamphlet    [Patent Document 51] WO 03029184 pamphlet    [Patent Document 52] WO 03029205 pamphlet    [Patent Document 53] WO 04026817 pamphlet    [Patent Document 54] WO 04074297 pamphlet    [Patent Document 55] WO 05021503 pamphlet    [Patent Document 56] Japanese Patent Application Laid-Open No. 2004-307439    [Patent Document 57] Japanese Patent Application Laid-Open No. 2004-307440    [Patent Document 58] Japanese Patent Application Laid-Open No. 2004-307441    [Patent Document 59] Japanese Patent Application Laid-Open No. 2004-307442    [Patent Document 60] WO 06041015 pamphlet    [Patent Document 61] Japanese Patent Application Laid-Open No. 2004-137208    [Patent Document 62] Japanese Patent Application Laid-Open No. 2005-41867    [Patent Document 63] Japanese Patent Application Laid-Open No. 2005-47899    [Patent Document 64] WO 05040091 pamphlet    [Patent Document 65] WO 05063671 pamphlet    [Patent Document 66] WO 05079788 pamphlet    [Non-patent Document 1] S. Mandalaetal., Science, 296, 346 (2002).    [Non-patent Document 2] V. Brinkmann et al., J. Biol. Chem., 277, 21453 (2002).    [Non-patent Document 3] M. G. Sanna et al., J. Biol. Chem., 279, 13839 (2004).    [Non-patent Document 4] M. Forrestetal., J. Pharmacol. Exp. Ther., 309, 758 (2004).    [Non-patent Document 5] B. Levkau et al., Circulation, 110, 3358 (2004).    [Non-patent Document 6] S. Salomoneet al., Eur. J. Pharmacol. 469, 125 (2003).    [Non-patent Document 7] Y. Gon et al., PNAS 102, 9270 (2005).